Antiparasitic milbemycin and avermectin derivatives

ABSTRACT

8,9 and/or 14,15 epoxidized and 5-acylated milbemycins and avermectins are prepared from the parent milbemycins and avermectins by epoxidation and acylation (in either order). They have enhanced anthelmintic, acaricidal and insecticidal activities.

BACKGROUND TO THE INVENTION

The present invention relates to a series of new macrolide compoundswhich are derivatives of certain known milbemycin and avermectinderivatives. These compounds have valuable acaricidal, insecticidal andanthelmintic activities. The invention also provides methods ofpreparing these compounds and compositions and methods for using them.

The milbemycins are a series of macrolide compounds known to haveanthelmintic, acaricidal and insecticidal activities. Milbemycin D wasdisclosed in U.S. Pat. No. 4,346,171, where it was referred to as"Compound B-41D", and milbemycins A₃ and A₄ were disclosed in U.S. Pat.No. 3,950,360. These compounds may be represented by the formula (A):##STR1## in which R¹ represents a methyl group, an ethyl group or anisopropyl group, these compounds being designated as milbemycin A₃,milbemycin A₄ and milbemycin D, respectively. For the avoidance ofdoubt, formula (A) also shows the numbering of positions of themacrolide ring system applied to those positions most relevant to thecompounds of the present invention.

Subsequently, various derivatives of the original milbemycins have beenprepared and their activities investigated. For example, epoxymilbemycins have been disclosed in Japanese patent applications Kokai(i.e. laid open to public inspection) No. 57-139079, 57-139080, 59-33288and 59-36681 and in U.S. Pat. No. 4,530,921. 5-Esterified milbemycinshave been disclosed in U.S. Pat. No. 4,201,861, No. 4,206,205, No.4,173,571, No. 4,171,314, No. 4,203,976, No. 4,289,760, No. 4,457,920,No. 4,579,864 and No. 4,547,491, in European Patent Publications No.8184, No. 102,271, No. 115,930, No. 180,539 and No. 184,989 and inJapanese patent applications Kokai No. 57-120589, 59-16894 and61-180787.

Like the milbemycins, the avermectins are based upon the same16-membered ring macrolide compound. The avermectins are disclosed, forexample in J. Antimicrob. Agents Chemother., 15(3), 361-367 (1979).These compounds may be represented by the formula (B): ##STR2## in whichR¹ represents an isopropyl group or a sec-butyl group, these compoundsbeing designated as avermectin B_(1b) and avermectin B_(1a),respectively.

22,23-Dihydroavermectins B_(1a) and B_(1b) may be obtained by reductionof the double bond between the 22 and 23 positions and are disclosed inU.S. Pat. No. 4,199,569.

We have now discovered that certain esterified and epoxidizedderivatives of these milbemycins and avermectins have unexpectedlypotent acaricidal, insecticidal and anthelmintic activities.

BRIEF SUMMARY OF INVENTION

The compounds of the invention are those compounds of formula (I):##STR3## in which:

the broken line represents a single or double carbon-carbon bond betweenthe carbon atoms at the 22 and 23 positions;

R¹ represents a methyl group, an ethyl group, an isopropyl group or asec-butyl group;

R² represents a hydrogen atom or a4'-(α-L-oleandrosyl)-α-L-oleandrosyloxy group;

R³ represents a pharmaceutically, agriculturally or veterinarilyacceptable organic acid residue capable of forming an ester group;

one of A and B represents an oxygen atom; and

the other of A and B represents an oxygen atom or a double bond betweenthe two carbon atoms to which it is shown as attached.

The compounds of the invention may be prepared from a compound offormula (II): ##STR4## (in which the dotted line and R¹ and R² are asdefined above) by subjecting said compound of formula (II) in any orderto the steps:

(a) oxidation to convert at least one of the double bonds at the 8, 9and 14, 15 positions to an epoxy group; and

(b) esterification at the 5-position with an acid of formula (III):

    R.sup.3 OH                                                 (III)

(in which R³ is as defined above) or with a reactive derivative thereof.

The invention still further provides an anthelmintic, acaricidal andinsecticidal composition comprising an anthelmintic, acaricidal andinsecticidal compound in admixture with a pharmaceutically,agriculturally, veterinarily or horticulturally acceptable carrier ordiluent, wherein said compound is selected from the group consisting ofcompounds of formula (I).

The invention still further provides a method of treating an animal,which may be human or non-human, parasitized by a parasite selected fromthe group consisting of helminths, acarids and insects, which comprisesapplying to or administering to said animal an active compound, whereinsaid active compound is selected from the group consisting of compoundsof formula (I).

The invention still further provides a method of protecting animals orplants from damage by parasites selected from the group consisting ofacarids, helminths and insects, which comprises applying an activecompound to said animals, to said plants or to seeds of said plants orto a locus including said animals, plants or seeds, wherein the activecompound is selected from the group consisting of compounds of formula(I).

DETAILED DESCRIPTION OF INVENTION

Preferred classes of compounds of the present invention are as follows:

1. Where the broken line between the 22 and 23 positions represents asingle bond, R¹ represents a methyl group, an ethyl group or anisopropyl group and R² represents a hydrogen atom.

2. Where the broken line between the 22 and 23 positions represents asingle bond, R¹ represents an isopropyl group or a sec-butyl group andR² represents a 4'-(α-L-oleandrosyl)-α-L-oleandrosyloxy group.

3. Where the broken line between the 22 and 23 positions represents adouble bond, R¹ represents an isopropyl group or a sec-butyl group andR² represents a 4'-(α-L-oleandrosyl)-α-L-oleandrosyloxy group.

R³ represents a residue of a pharmaceutically acceptable organic acidwhich is capable of forming an ester with the hydroxy group at the5-position of the parent milbemycin. Examples of such organic acidsinclude, for example, the carboxylic acids, carbonic acids, carbamicacids, sulfonic acids and phosphoric acids.

Preferred groups which may be represented by R³ include the groupshaving the following formulae:

    --CO--(O).sub.n --R.sup.4                                  1.

in which:

n represents the cypher 0 or the integer 1; and

R⁴ represents a C₁ -C₁₈ alkyl group, a C₃ -C₈ cycloalkyl group, a C₇ -C₉aralkyl group, a C₂ -C₁₇ alkenyl group, a C₂ -C₆ alkynyl group, a C₆-C₁₀ aryl group or a heterocyclic group having from 5 to 10 ring atomsof which at least one is a hetero-atom selected from the groupconsisting of nitrogen, oxygen and sulfur atoms, said alkyl, alkenyl andalkynyl groups being unsubstituted or having at least one substituentselected from the group consisting of substituents (a):

substituents (a): alkoxy groups, halogen atoms, alkoxycarbonyl groups,carboxylic acyloxy groups, hydroxy groups, carboxy groups, amino groups,alkylamino groups, dialkylamino groups, trialkylamino groups, carboxylicacylamino groups, cyano groups, carbamoyl groups, alkylcarbamoyl groups,dialkylcarbamoyl groups, mercapto groups, alkylthio groups,alkylsulfinyl groups, alkylsulfonyl groups, nitro groups, phenoxygroups, halophenoxy groups, alkylsulfonyloxy groups, arylsulfonyloxygroups, thiocyanato groups and heterocyclic groups having 5 or 6 ringatoms of which at least one is a hetero-atom selected from the groupconsisting of nitrogen, oxygen and sulfur atoms;

and said cycloalkyl, aralkyl and aryl groups being unsubstituted orhaving at least one substituent selected from the group consisting ofsubstituents (a) and substituents (b):

substituents (b): alkyl groups, alkoxyalkyl groups and haloalkyl groups;

and said heterocyclic groups being unsubstituted or having at least onesubstituent selected from the group consisting of substituents (a),substituents (b) and oxygen atoms;

where groups in said substituents (a) and substituents (b) containcarbon atoms, the maximum number of carbon atoms in each such group is 9and said groups defined in substituents (a) and substituents (b) beingunsubstituted or having at least one further substituent selected fromthe group consisting of substituents (a) and substituents (b) providedsaid further substituent is not itself further substituted.

    --CO--NR.sup.5 R.sup.6                                     2.

in which R⁵ and R⁶ are independently selected from the group consistingof hydrogen atoms, C₁ -C₆ alkyl groups, C₂ -C₆ alkenyl groups, C₇ -C₉aralkyl groups and C₆ -C₁₀ aryl groups, said groups being unsubstitutedor having at least one substituent as defined for the correspondinggroup represented by R⁴.

    --SO.sub.2 R.sup.7                                         3.

in which R⁷ represents a C₁ -C₆ alkyl group or a C₆ -C₁₀ aryl group,said groups being unsubstituted or having at least one substituent asdefined for the corresponding group represented by R⁴.

    --(Y.sup.1 ═)P(--Y.sup.2 --R.sup.8)--Y.sup.3 --R.sup.9 4.

in which:

Y¹, Y² and Y³ are independently selected from the group consisting ofoxygen atoms and sulfur atoms; and

R⁸ and R⁹ are independently selected from the group consisting of C₁ -C₆alkyl groups and C₁ -C₆ alkyl groups having at least one substituentselected from the group consisting of substituents (a).

Where R⁴ represents an alkyl group, this may be a straight or branchedchain alkyl group having from 1 to 18 carbon atoms and examples of suchgroups include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, t-butyl, pentyl, isopentyl, heptyl, octyl, decyl, undecyl,dodecyl, tridecyl, pentadecyl, hexadecyl, heptadecyl and octadecylgroups.

Where R⁴ represents a cycloalkyl group, this may be a monocyclic orfused polycyclic (preferably bicyclic) ring system containing from 3 to8 ring carbon atoms and examples include the cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl andbicyclo[2.2.1]heptyl groups.

Where R⁴ represents an aralkyl group containing from 7 to 9 carbonatoms, examples of such groups include the benzyl, phenethyl,3-phenylpropyl, α-methylbenzyl and α,α-dimethylbenzyl groups.

Where R⁴ represents an alkenyl group, this may be a straight or branchedchain group containing from 2 to 17, preferably from 2 to 6, carbonatoms and having at least one double bond. Examples include the vinyl,1-propenyl, 2-propenyl, isopropenyl, 1-methyl-1-propenyl, 9-decenyl,8-heptadecenyl, 8,11-heptadecadienyl, 8,11,14-heptadecatrienyl and8-pentadecenyl groups.

Where R⁴ represents an alkynyl group containing from 2 to 6 carbonatoms, this may be a straight or branched chain group and examplesinclude the ethynyl, 1-propynyl and 2-propynyl groups.

Where R⁴ represents an aryl group containing from 6 to 10 carbon atoms,examples of such groups include the phenyl, 1-naphthyl and 2-naphthylgroups.

Where R⁴ represents a heterocyclic group, it contains from 5 to 10 ringatoms, of which at least one, and preferably from 1 to 3, arehetero-atoms selected from the group consisting of nitrogen, oxygen andsulfur atoms. The ring system may be a monocyclic or fused polycyclic(preferably bicyclic) ring system and examples of the heterocyclicgroups which may be represented by R⁴ include the furyl, thienyl,pyrrolyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl,imidazolyl, pyrazolyl, pyranyl, triazolyl, triazinyl, quinazolyl,tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl,piperazinyl, morpholinyl, thiomorpholinyl, tetrahydroquinolyl,quinuclidinyl and thienofuranyl groups.

Examples of substituents which may be present on any of the above groupswhich may be represented by R⁴ include: such alkyl groups as the methyl,ethyl, isopropyl and t-butyl groups; such alkoxy groups as the methoxy,ethoxy and isopropoxy groups; such alkoxyalkyl groups as themethoxymethyl group; such alkoxycarbonyl groups as the methoxycarbonyland ethoxycarbonyl groups; such haloalkyl groups as the chloromethyl,fluoromethyl, trichloromethyl, trifluoromethyl and 2-chloroethyl groups;such halo groups as the fluoro, chloro, bromo and iodo groups; thehydroxy, carboxy and amino groups; such alkylamino and alkylammoniumgroups as the methylamino, dimethylamino, diethylamino, diisopropylaminoand diethyl(methyl)ammonium groups; such lower aliphatic carboxylicacylamino groups as the acetamido and trifluoroacetamido groups; thecyano and carbamoyl groups; such alkylcarbamoyl groups as themethylcarbamoyl and dimethylcarbamoyl groups; such lower aliphaticcarboxylic acyloxy groups as the fluoroacetoxy and trichloroacetoxygroups; such substituted lower alkoxycarbonyl groups as theβ,β,β-trichloroethoxycarbonyl group; the mercapto, methylthio,thiocyanato, methanesulfinyl, methanesulfonyl, nitro, phenoxy andp-chlorophenoxy groups; such substituted alkoxy groups as the2,2-dimethyl-1,3-dioxolanylmethoxy group; and such heterocycliccarbonyloxy groups as the 3,4-dihydro-2H-pyran-2-carbonyloxy and3,4,5,6-diisopropylidine-D-galactouronyloxy groups; as well as the 5-and 6-membered compounds amongst the heterocyclic groups defined for R⁴.

Where R⁵, R⁶, R⁷, R⁸ or R⁹ represents a C₁ -C₆ alkyl group, this may bea straight or branched chain group and examples include the methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, pentyl,isopentyl, hexyl and isohexyl groups.

Where R⁵, R⁶ or R⁷ represents an aryl group or R⁵ or R⁶ represents analkenyl or aralkyl group, these may be exemplified above in relation toR⁴.

Particularly preferred groups which may be represented by R³ include theacetyl, propionyl, chloroacetyl, trichloroacetyl, trifluoroacetyl,acetoxyacetyl, chloropropionyl, chlorobenzoyl, ethoxycarbonyl,methoxycarbonyl, chloromethoxycarbonyl, dichloromethoxycarbonyl,(3,4-dihydro-2H-pyran-2-carbonyloxy) methoxycarbonyl,(3,4,5,6-diisopropylidene-D-galactouronyloxy) methoxycarbonyl,(2,2-dimethyl-1,3-dioxolanylmethoxy)methoxycarbonyl,hydroxybutyryloxymethoxycarbonyl, carboxypropionyl,(1H-1,2,4-triazol-1-yl)acetyl, diethylaminoacetyl,(iodomethyldiethylammonio)acetyl, methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl, methanesulfonyl, p-toluenesulfonyl,benzenesulfonyl, diethylthiophosphoryl, dimethylphosphoryl,diethylphosphoryl, fluorobenzoyl, butyryl, valeryl, hexanoyl, octanoyl,hexadecanoyl, isobutyryl, isovaleryl, pivaloyl, acryloyl, benzoyl,bromoacetyl, allyloxycarbonyl, iodoacetyl, propionyloxyacetyl,hydroxyacetoxyacetyl, (benzamidoacetoxy)acetyl, cinnamoyl,(trifluoromethyl)benzoyl, iodobenzoyl, toluoyl, methoxybenzoyl,dichlorobenzoyl, (chlorobenzyloxy)acetyl, (pyrrolylcarbonyloxy)acetyl,fluorobenzoyl, nicotinoyl, isonicotinoyl, picolinoyl, nitrobenzoyl andthiocyanatoacetyl groups.

Examples of various preferred compounds of the invention are givenhereafter in the Examples. In addition to these, various other preferredcompounds include:

8,9-Epoxy-5-O-acetylmilbemycin D

8,9-Epoxy-5-O-acetylmilbemycin A₃

8,9-Epoxy-5-O-acetyl-22,23-dihydroavermectin B_(1a)

8,9-Epoxy-5-O-acetyl-22,23-dihydroavermectin B_(1b)

8,9-Epoxy-5-O-acetylavermectin B_(1a)

8,9-Epoxy-5-O-acetylavermectin B_(1b)

8,9-Epoxy-5-O-propionylmilbemycin D

8,9-Epoxy-5-O-chloroacetylmilbemycin A₃

8,9-Epoxy-5-O-trichloroacetylmilbemycin D

8,9-Epoxy-5-O-trichloroacetyl-22,23-dihydroavermectin B_(1a)

8,9-Epoxy-5-O-trichloroacetylavermectin B_(1a)

8,9-Epoxy-5-O-trifluoroacetyl-22,23-dihydroavermectin B_(1a)

8,9-Epoxy-5-O-acetoxyacetylmilbemycin A₄

8,9-Epoxy-5-O-(α-chloropropionyl)avermectin B_(1a)

8,9-Epoxy-5-O-(p-chlorobenzoyl)milbemycin A₄

8,9-Epoxy-5-O-ethoxycarbonyl-22,23-dihydroavermectin B_(1a)

8,9-Epoxy-5-O-dichloromethoxycarbonylmilbemycin A₄

8,9-Epoxy-5-O-(3,4-dihydro-2H-pyran-2-carbonyloxy)methoxycarbonylmilbemycinD

8,9-Epoxy-5-O-(3,4,5,6-diisopropylidine-D-galactouronyloxy)methoxycarbonylmilbemycinA₄

8,9-Epoxy-5-O-(2,2-dimethyl-1,3-dioxolanylmethoxy)methoxycarbonylmilbemycinA₄

8,9-Epoxy-5-O-4'-hydroxybutyryloxymethoxycarbonylmilbemycin A₄

8,9-Epoxy-5-O-carboxypropionylmilbemycin A₄

Sodium 8,9-epoxy-5-O-carboxylatopropionylmilbemycin D

8,9-Epoxy-5-O-(1H-1,2,4-triazol-1-yl)acetylmilbemycin A₄

8,9-Epoxy-5-O-diethylaminoacetylmilbemycin A₄

8,9-Epoxy-5-O-(iodomethyldiethylammonio)acetylmilbemycin A₄

8,9-Epoxy-5-O-methylcarbamoylmilbemycin A₄

8,9-Epoxy-5-O-methanesulfonylmilbemycin A₄

8,9-Epoxy-5-O-p-toluenesulfonylmilbemycin D

8,9-Epoxy-5-O-diethylthiophosphorylmilbemycin D

8,9-Epoxy-5-O-dimethylphosphorylmilbemycin A₄

14,15-Epoxy-5-O-methoxycarbonylmilbemycin A₄

14,15-Epoxy-5-O-methanesulfonylmilbemycin D

8,9,14,15-Diepoxy-5-O-trichloroacetylmilbemycin A₄

8,9,14,15-Diepoxy-5-O-trichloroacetyl-22,23-dihydroavermectin B_(1a)

8,9,14,15-Diepoxy-5-O-p-fluorobenzoylavermectin B_(1a)

8,9,14,15-Diepoxy-5-O-methanesulfonylmilbemycin A₄

The most preferred compounds of the invention are:

8,9-epoxy-5-O-propionylmilbemycin A₄₊₃

8,9-epoxy-5-O-α-chloropropionylmilbemycin A₄₊₃ and

8,9-epoxy-5-O-trifluoroacetylmilbemycin A₄.

Preparation of the compounds of the invention may be carried out asindicated in the following reaction scheme: ##STR5##

In the above formulae, R¹, R², R³, A, B and the broken line are asdefined above.

STEPS A AND D

In these steps, the compounds of formulae (II) and (V), respectively,are epoxidized with a mild oxidizing agent to convert one or both of thedouble bonds at the 8,9 and 14,15 positions to an epoxy group. Certainof the compounds of formula (IV), their use and the preparative methodinvolved in Step A are disclosed in Japanese Patent Applications KokaiNo. 57-139079, 57-139080 and 59-36681 and in U.S. Pat. No. 4,530,921,the disclosures of which are incorporated herein by reference.

In these steps, the mild oxidizing agent is preferably either: aperacid, such as m-chloroperbenzoic acid; or an alkyl hydroperoxide,such as t-butyl hydroperoxide, in association with a metalacetylacetonate, such as vanadium oxyacetylacetonate, as catalyst. Suchepoxidation reactions are well known for this type of compound and thereis no particular limitation on the nature of the oxidizing agentemployed. However, where it is desired to epoxidize only the 8,9 doublebond, we prefer to carry this out using from 1 to 2 equivalents of thealkyl hydroperoxide catalyzed by a metal acetylacetonate. Where it isdesired to epoxidize only the 14,15 double bond, it is desirable to usefrom 1 to 2 equivalents of a peracid. Where it is desired to epoxidizeboth the 8,9 and 14,15 double bonds to produce a diepoxy derivative,there is no particular limitation on the nature of the oxidizing agent,although we prefer to use from 2 to 3 equivalents of such an oxidizingagent. If a much greater excess of oxidizing agent is used, theoxidation reaction can give rise to the 3,4,8,9,14,15-triepoxyderivative as a by-product.

The reaction is preferably carried out in the presence of a solvent, thenature of which is not critical, provided that it does not interferewith the reaction and is not readily oxidized under conditions of thereaction. Suitable solvents include, for example: hydrocarbons,particularly aliphatic and aromatic hydrocarbons, such as hexane,benzene or toluene; and halogenated hydrocarbons, particularlyhalogenated aliphatic hydrocarbons, such as methylene chloride orchloroform. The reaction will take place over a wide range oftemperatures and the precise temperature chosen is not critical to theinvention; however, we generally find it convenient to carry out thereaction at a temperature of from 0° to 40° C. and preferably at aboutroom temperature. The time required for the reaction may vary widely,but a period of from 1 to 6 hours will normally suffice.

STEPS B AND C

In these steps, the compound of formula (IV) or (II), respectively, isacylated at its 5-position with a carboxylic acid of formula (III) orwith a reactive derivative thereof, to give a compound of formula (I) of(V) respectively.

Some of the compounds of formula (V), their use and their preparation asin Step C are known from Japanese Patent Application Kokai No. 57-139081and 59-36681 and from U.S. Pat. No. 4,173,571 and 4,171,314, thedisclosures of which are incorporated herein by reference.

The acylation reaction may be carried out by methods well known for thistype of reaction using either the free acid of formula (III) or areactive derivative thereof. Examples of reactive derivatives include:acid halides, such as the acid chloride, acid bromide or acid iodide;acid anhydrides; mixed acid anhydrides; active esters, such as thep-nitrobenzyl ester; and active amides.

The reaction is preferably carried out in the presence of a solvent, thenature of which is not critical, provided that it has no adverse effectupon the reaction. Examples of suitable solvents include: hydrocarbons,which may be aliphatic or aromatic, such as hexane, benzene or toluene;halogenated hydrocarbons, particularly halogenated aliphatichydrocarbons, such as methylene chloride or chloroform; ethers, such asdiethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone ormethyl ethyl ketone; nitriles, such as acetonitrile; and esters, such asethyl acetate. The reaction will take place over a wide range oftemperatures and the precise temperature chosen is not critical to theinvention. However, we generally find it convenient to carry out thereaction at a temperature of from 0° to 80° C. and more preferably at atemperature of from 10° to 30° C. The time required for the reaction mayvary widely, depending upon many factors; however, at a temperaturewithin the suggested ranges, a period of from 1 to 6 hours will normallysuffice.

We generally prefer to employ from 1 to 10 equivalents, more preferablyfrom 1.5 to 4 equivalents, of the acid (III) or its reactive derivative,per mole of the compound of formula (II) or (IV).

Where the acid (III) itself is employed, the reaction is preferablyeffected in the presence of a dehydrating agent, such asdicyclohexylcarbodiimide, p-toluenesulfonic acid or sulfuric acid. Wherea reactive derivative of the acid (III) is employed, we prefer to carryout the reaction in the presence of a base, which serves to acceleratethe reaction. Examples of suitable bases include: such organic bases aspyridine, triethylamine and 4-dimethylaminopyridine; and such inorganicbases as potassium carbonate or sodium carbonate.

After completion of each or both of the steps of the reaction sequence,the resulting product can be recovered from the reaction mixture byconventional means and, if necessary, may be further purified by suchconventional means as the various chromatography techniques,particularly column chromatography.

Surprisingly, we have found that the yield in epoxidation Step D is verymuch better than that in the known epoxidation Step A. Accordingly, thepreferred reaction sequence comprises Step C followed by Step D.

The starting material of formula (II) may be a single isolated compoundor it may be a mixture of two or more such compounds, which may be usedwithout separation. For example, mixtures of milbemycins A₃ and A₄ arereadily available and may easily be used.

The compounds of the invention have a strong acaricidal activityagainst, for example, adults, imagos and eggs of Tetranychus, Panonychus(e.g. Panonychus ulmi and Panonychus citri), Aculopa pelekassi and rustmites, which are parasitic to fruit trees, vegetables and flowers. Theyare also active against Ixodidae, Dermanyssidae and Sarcoptidae, whichare parasitic to animals. Further, they are active against:exoparasites, such as Oestrus, Lucilia, Hypoderma, Gautrophilus, liceand fleas, which are parasitic to animals and birds, particularlylivestock and poultry; domestic insects, such as cockroaches andhouseflies; and various harmful insects in agricultural andhorticultural areas, such as aphids and larval Lepidoptera. They arealso effective against Meloidogyne in the soil, Bursaphelenchus andPhizoglyphus. They are also effective against insects of the ordersColeoptera, Homoptera, Heteroptera, Diptera, Thysanoptera, Orthoptera,Anoplura, Siphonaptera, Mallophage, Thysanura, Isoptera, Psocoptera, andHymenoptera.

The compounds of the invention equally can be used to control otherplant-damaging insects, particularly insects that damage plants byeating them. The compounds can be used to protect both ornamental plantsand productive plants, particularly cotton (e.g. against Spodopteralittoralis and Heliothis virescens), as well as vegetable crops (e.g.against Leptinotarsa decemlineata and Myzus persicae) and rice crops(e.g. against Chilo suppressalis and Laodelphax).

The activity of the compounds of the invention is pronounced, bothsystemically and by contact. Accordingly, the compounds are veryeffective against sucking insects, especially sucking insects of theorder Homoptera and most particularly the family Aphididae (such asAphis fabae, Aphis craccivora and Myzus persicae), which are difficultto control with known compositions.

Accordingly, the compounds of the invention can be used to treat allmanner of plants (as well as the seeds from which such plants are grownand the environment, whether for growth or storage, containing suchplants) to protect them from insects such as those exemplified above.Such plants include cereals (e.g. maize or rice), vegetables (e.g.potatoes or soybeans), fruits and other plants (e.g. cotton).

The compounds of the invention can similarly be used to protect animalsfrom a variety of ectoparasites, by applying the compounds to theanimals or to the animals' environment, e.g. livestock housing, animalboxes, abattoirs, pasture land and other grasslands, as well as to anyother places liable to be infested. The compounds may also be applied toexternal parts of the animals, preferably before they are infested.

Moreover, the compounds of the invention are effective against variousparasitical helminths. These parasites can attack livestock, poultry andpet animals (such as pigs, sheep, goats, cows, horses, dogs, cats andfowl) and can cause grave economic damage. Among the helminths, thenematodes in particular often cause serious infection. Typical genera ofnematodes which are parasitic on these animals and against which thecompounds of the invention are effective include:

Haemonchus,

Trichostrongylus,

Ostertagia,

Nematodirus,

Cooperia,

Ascaris,

Bunostomum,

Oesophagostomum,

Chabertia,

Trichuris,

Strongylus,

Trichonema,

Dictyocaulus,

Capillaria,

Heterakis,

Toxocara,

Ascaridia,

Oxyuris,

Ancylostoma,

Uncinaria,

Toxascaris and

Parascaris.

Certain parasitical species of the genera Nematodirus, Cooperia andOesophagostomum attack the intestines, while certain species of thegenera Haemonchus and Ostertagia parasitize the stomach, and parasitesbelonging to the genus Dictyocaulus are found in the lungs. Parasitesbelonging to the families Filariidae and Setariidae are found ininternal tissues and organs, for example, the heart, the blood vessels,the subcutaneous tissues and the lymphatic vessels. The compounds of theinvention are active against all these parasites.

The compounds of the invention are also effective against parasiteswhich infect humans. Typical of the parasites which may most commonly befound in the digestive tracts of human beings are parasites of thegenera Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella,Capillaria, Trichuris and Enterobius. The compounds are also activeagainst parasites of the genera Wuchereria, Brugia, Onchocerca and Loaof the family Filariidae (which are found in blood, tissues and organsother than the digestive tract and are medically important), parasitesof the genus Dracunculus of the family Dracunculidae and parasites ofthe genera Strongyloides and Trichinella, which in a particular statemay parasitize outside the intestinal tract, although they areessentially intestinal parasites.

The form of the compositions of the invention and the nature of thecarriers or diluents employed in them will vary depending upon theintended use of the composition. For example, where the compounds of theinvention are to be employed as anthelmintics, they are preferablyadministered orally, parenterally or topically and the form ofcompositions chosen will be appropriate to the intended route ofadministration.

For oral administration, the composition of the invention is preferablyin the form of a liquid drink comprising a non-toxic solution,suspension or dispersion of the active compound in admixture with asuspending agent (such as bentonite), a wetting agent or other diluents,preferably in water or another non-toxic solvent. The drink, in general,also contains an anti-foaming agent. The active compound would normallybe present in the drink in an amount of from 0.01 to 0.5% by weight,more preferably from 0.01 to 0.1% by weight.

Compositions for oral administration may also be in the form of drysolids, preferably in unit dosage form, such as capsules, pills ortablets containing the desired amount of the active compound. Thesecompositions may be prepared by mixing the active compound uniformlywith suitable diluents, fillers, disintegrators and/or binding agents,for example starch, lactose, talc, magnesium stearate and vegetable gum.The weight and contents of the preparation will vary widely, dependingupon the nature of the animal to be treated, the degree of infection,the nature of the parasite and the body weight of the animal to betreated.

The compounds may also be administered as an additive to animalfeedstuffs, in which case they may be dispersed uniformly in thefeedstuffs, used as a top dressing or used in the form of pellets. Thecontent of active compound in the feedstuff is preferably from 0.0001 to0.02%, in order to achieve the desired anthelmintic activity.

For parenteral administration, the compound of the invention ispreferably dissolved or suspended in a liquid vehicle, preferably avegetable oil, such as peanut oil or cottonseed oil. Where the compoundis a salt of a compound of formula (II), the liquid vehicle may be wateror another aqueous medium. Depending upon the animal to be treated, theinjection may be subcutaneous or into the proventriculus, a muscle orthe trachea. Such preparations would normally contain the activecompound at a concentration of from 0.05 to 50% by weight.

The compounds of the invention may also be administered topically inadmixture with a suitable carrier, such as dimethyl sulphoxide or ahydrocarbon solvent. Such preparations would be applied directly to theoutside of the animal by spraying (e.g. by a hand spray or in sprayraces), by dipping (e.g. in a plunge dip), by a pour-on solution or bymanual methods (e.g. hand-dressing).

The dose of active compound may be varied, depending upon the nature ofthe animal to be treated, and the nature and degree of parasiticinfection. However, best results for oral administration are achievedwhen the dose is from 0.01 to 100 mg, more preferably from 0.5 to 50 mg.per 1 kg body weight. The compound may be administered in a single doseor in divided doses for a relatively short period, such as from 1 to 5days.

Where the composition of the invention is intended for agricultural orhorticultural use, a variety of forms and formulations is possible. Forexample, the composition may be formulated as dusts, coarse dusts,soluble powders, microgranules, fine microgranules, wettable powders,dilute emulsions, emulsifiable concentrates, aqueous or oilysuspensions, dispersions or solutions (which may be directly sprayableor for dilution), aerosols or capsules in, for example, polymericsubstances. The carrier employed may be natural or synthetic and organicor inorganic; it is generally employed to assist the active compound toreach the substrate to be treated, and to make it easier to store,transport or handle the active compound. Solid, liquid and gaseouscarriers may be employed, chosen from carriers well known in the art foruse with compositions of this type.

Such formulations may be prepared by conventional means, e.g. byintimate mixing and/or grinding of the active ingredient(s) with thecarrier or diluent, e.g. solvent, solid carrier or, optionally,surface-active agent.

Suitable solvents include: aromatic hydrocarbons, preferably the C₈ toC₁₂ fractions from petroleum distillation, such as xylene mixtures orsubstituted naphthalenes; esters of phthalic acid, such as dibutyl ordioctyl phthalate; aliphatic hydrocarbons, such as cyclohexane or theparaffins; alcohols and glycols or esters thereof, such as ethanol,ethylene glycol, ethylene glycol monomethyl ether or ethylene glycolmonoethyl ether; ketones, such as cyclohexanone; strongly polarsolvents, such as N-methyl-2-pyrrolidone, dimethyl sulfoxide orN,N-dimethylformamide; optionally epoxidized vegetable oils, such asepoxidized coconut oil or soybean oil; and water.

Solid carriers, which may be used, for example, in dusts and dispersiblepowders, include natural mineral fillers, such as calcite, talc, kaolin,montmorillonite or attapulgite. In order to improve the physicalproperties of the composition, it is also possible to add highlydispersed silicic acid or highly dispersed absorbent polymers. Suitablegranulated adsorptive carriers may be porous (such as pumice, groundbrick, sepiolite or bentonite) or non-porous (such as calcite or sand).A wide variety of pregranulated materials, organic or inorganic, mayalso be used; examples include dolomite and ground plant residues.

Surface-active agents which may be used are well known in the art andmay be non-ionic, cationic or anionic agents having good emulsifying,dispersing and wetting properties. Mixtures of such agents may also beused.

Compositions may also contain stabilizers, anti-foaming agents,viscosity regulators, binders or adhesives or any combination thereof,as well as fertilizers or other active substances to achieve specialeffects.

Pesticidal compositions will generally contain: from 0.01 to 99%, morepreferably from 0.1 to 95%, by weight of the active compound; from 1 to99.99% of a solid or liquid additive; and from 0 to 25%, more preferablyfrom 0.1 to 25%, of a surface-active agent. Whereas commercial productsare generally sold as concentrated compositions, they are generallydiluted by the end-user to a concentration of from 0.001 to 0.0001% byweight (from 10 to 1 ppm).

The compounds of the invention have, surprisingly, been found to be mostespecially effective against mites on plants.

The invention is further illustrated by the following Examples, of whichExamples 1-55 illustrate the preparation of various compounds of theinvention and Examples 56 and 57 illustrate their biological activity.Where mixtures of compounds, e.g. milbemycins A₄ +A₃, are used, theratios indicated in association with them are molar ratios. In allcolumn chromatography reported hereafter, the eluent used was a 3:1 byvolume mixture of hexane and ethyl acetate.

EXAMPLE 1 8,9-Epoxy-5-O-acetylmilbemycin A₄ (R¹ =C₂ H₅, R² =H, R³=acetyl)

0.55 ml of a 3 molar toluene solution of t-butyl hydroperoxide was addeddropwise to a solution of 638 mg of 5-O-acetylmilbemycin A₄ and 30 mg ofvanadium oxyacetylacetonate in 22 ml of dry benzene, whilst ice-cooling,and then the mixture was allowed to stand at room temperature for 2hours. The reaction mixture was then cooled with ice, poured into anaqueous solution of sodium sulfite and extracted with ethyl acetate. Theextracts were washed with water and then with a saturated aqueoussolution of sodium chloride, after which they were dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was subjected to column chromatography throughsilica gel, to give 353 mg of the title compound.

Mass spectrum (m/z): 600 (M⁺), 584 (M⁺ --H₂ O), 540 (M⁺ +1--H₂O--COCH₃).

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:

3.08 (1H, doublet of triplets, J=2.9 & 8.7 Hz, C₂₅ H);

3.37 (1H, quartet, J=2.6 Hz, C₂ H);

3.57 (1H, doublet, J=9.6 Hz, C₉ H);

3.64 (1H, multiplet, C₁₇ H);

3.83 (1H, singlet, C₇ OH);

3.90 (1H, doublet, J=11.2 Hz, C₂₇ H);

4.23 (1H, doublet, J=4.8 Hz, C₆ H);

4.39 (1H, doublet, J=11.2 Hz, C₂₆ H);

4.98 (1H, doublet of doublets, J=9.3 & 9.6 Hz, C₁₀ H);

5.08 (1H, multiplet, C₁₅ H);

5.28 (1H, multiplet, C₁₉ H);

5.48 (1H, multiplet, C₃ H);

5.64 (1H, multiplet, C₅ H);

5.85 (1H, doublet of doublets, J=9.3 & 14 Hz, C₁₁ H).

Following the procedure described in Example 1, the compounds ofExamples 2 to 43 were prepared. These compounds may be represented bythe following formula (Ia): ##STR6## in which R¹, R² and R³ are asdefined in the following Table. In this Table and hereafter, the nuclearmagnetic resonance (NMR) results are given only for the C₉ hydrogen atomand the abbreviations used are as follows:

d=doublet

dd=doublet of doublets

m=multiplet.

    ______________________________________                                              R.sup.1                                                                 Exam- R.sup.2           m/z                                                   ples  R.sup.3           NMR (C.sub.9 H)                                       ______________________________________                                        2     R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (2.6:1)                                                    m/z: 614 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COC.sub.2 H.sub.5                                                                     NMR: 3.56 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.57 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            3     R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (2.6:1)                                                    m/z: 628 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COC.sub.3 H.sub.7                                                                     NMR: 3.56 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.57 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            4     R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (1.1:1)                                                    m/z: 642 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COC.sub.4 H.sub.9                                                                     NMR: 3.56 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.57 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            5     R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (1.8:1)                                                    m/z: 656 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COC.sub.5 H.sub.11                                                                    NMR: 3.56 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.57 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            6     R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (1.5:1)                                                    m/z: 640 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COC.sub.7 H.sub.15                                                                    NMR: 3.56 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3, 3.57 (1 H, d,                                             J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            7     R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (2.2:1)                                                    m/z: 796 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COC.sub.15 H.sub.31                                                                   NMR: 3.56 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3, 3.57 (1 H, d,                                             J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            8     R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (1.6:1)                                                    m/z: 628 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COCH(CH.sub.3).sub.2                                                                  NMR: 3.59 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.60 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            9     R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (3.4:1)                                                    m/z: 642 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COC(CH.sub.3).sub.3                                                                   NMR: 3.56 (1 H, d,                                                            J = 9.35 Hz, assigned to                                                      R.sup.1 = CH.sub.3), 3.57 (1 H, d,                                            J = 9.35 Hz, assigned to                                                      R.sup.1 = C.sub.2 H.sub.5)                            10    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (1.8:1)                                                    m/z: 612 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COCH═ CH.sub.2                                                                    NMR: 3.56 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.57 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            11    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (1.1:1)                                                    m/z: 540 (M.sup.+  + 1-                                     R.sup.2 = H       COC.sub.6 H.sub.5 -- H.sub.2 O, assigned                    R.sup.3 = COC.sub.6 H.sub.5                                                                     to R.sup.1 = C.sub.2 H.sub.5)                                                 NMR: 3.57 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.58 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            12    R.sup.1 = C.sub.2 H.sub.5                                                                       m/z: 634 (M.sup.+)                                          R.sup.2 = H       NMR: 3.57 (1 H, d,                                          R.sup.3 = COCH.sub.2 Cl                                                                         J = 9.35 Hz)                                          13    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (2.6:1)                                                    m/z: 678 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5 & Br = 79)                        R.sup.3 = COCH.sub.2 Br                                                                         NMR: 3.56 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.57 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            14    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (2:1)                                                      m/z: 702 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5 & Cl = 35)                        R.sup.3 = COCCl.sub.3                                                                           NMR: 3.57 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.59 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            15    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (4:1)                                                      m/z: 648 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5 & Cl = 35)                        R.sup.3 = COCHClCH.sub.3                                                                        NMR: 3.56 (1 H, d,                                                            J = 9.3 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.57 (1 H, d,                                            J = 9.3 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            16    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (1.8:1)                                                    m/z: 648 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COOC.sub.2 H.sub.5                                                                    NMR: 3.56 (1 H, d,                                                            J = 9.35 Hz, assigned to                                                      R.sup.1 = CH.sub.3), 3.57 (1 H, d,                                            J = 9.35 Hz, assigned to                                                      R.sup.1 = C.sub.2 H.sub.5)                            17    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (2:1)                                                      m/z: 642 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COOCH.sub.2 CH═ CH.sub.2                                                          NMR: 3.56 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3) 3.57 (1 H, d,                                             J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            18    R.sup.1 = C.sub.2 H.sub.5                                                                       m/z: 650 (M.sup.+, assigned to                              R.sup.2 = H       Cl = 35)                                                    R.sup.3 = COOCH.sub.2 Cl                                                                        NMR: 3.58 (1 H, d,                                                            J = 9.5 Hz)                                           19    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (1.7:1)                                                    m/z: 742 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = 3,4-dihydro-2H-                                                                       NMR: 3.57 (1 H, d,                                          pyran-2-carbonloxy-                                                                             J = 9.7 Hz)                                                 methoxycarbonyl                                                         20    R.sup.1 = sec-C.sub.4 H.sub.9 +                                                                 NMR: 3.61 (1 H, d,                                          i-C.sub.3 H.sub.7 (8:1)                                                                         J = 9.5 Hz) C.sub.3 H: 5.39                                                   (1 H, m)                                                    R.sup.2 = 4'-(α-L-oleand-                                                                 C.sub.10 H: 4.90 (1 H,                                      rosyl)-α-L-oleand-                                                                        dd, J = 5.9 & 9.5 Hz)                                       rosyloxy          C.sub.15 H: 5.11 (1 H, d,                                   R.sup.3 = COC.sub.2 H.sub.5                                                                     J = 9.4 Hz)                                           21    R.sup.1  = C.sub.2 H.sub.5 + CH.sub.3 (2.6:1)                                                   m/z: 726 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COCH.sub.2 I                                                                          NMR: 3.56 (1 H, d,                                                            J = 9.8 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.57 (1 H, d,                                            J = 9.8 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            22    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (2.2:1)                                                    m/z: 658 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COCH.sub.2 OCOCH.sub.3                                                                NMR: 3.56 (1 H, d,                                                            J = 9.8 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.57 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            23    R.sup.1 =  C.sub.2 H.sub.5 + CH.sub.3 (2.2:1)                                                   m/z: 672 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COCH.sub.2 OCOC.sub.2 H.sub.5                                                         NMR: 3.56 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.57 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            24    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (2.2:1)                                                    m/z: 674 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COCH.sub.2 OCOCH.sub.2 OH                                                             NMR: 3.56 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.57 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            25    R.sup. 1 = C.sub.2 H.sub.5 + CH.sub.3 (2.2:1)                                                   m/z: 541 (M.sup.+  - 236,                                   R.sup.2 = H       assigned to R.sup.1 = C.sub.2 H.sub.5)                      R.sup.3 = COCH.sub.2 OCOCH.sub.2                                                                NMR: 3.56 (1 H, d,                                          NHCOC.sub.6 H.sub.5                                                                             J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.57 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            26    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (2.2:1)                                                    m/z: 615 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = CONHCH.sub.3                                                                          NMR: 3.57 (1H, d,                                                             J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.59 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            27    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (3:1)                                                      m/z: 688 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COCH═ CH--C.sub.6 H.sub.5                                                         NMR: 3.57 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.59 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            28    R.sup.1 = C.sub.2 H.sub.5)                                                                      m/z: 730 (M.sup.+)                                          R.sup.2 = H       NMR: 3.60 (1 H, d,                                          R.sup.3 = CO-(p-CF.sub.3 --C.sub.6 H.sub.4)                                                     J = 9.5 Hz)                                           29    R.sup.1 = C.sub.2 H.sub.5                                                                       m/z: 696 (M.sup.+)                                          R.sup.2 = H       NMR: 3.59 (1 H, d,                                          R.sup.3 = CO-(p-Cl--C.sub.6 H.sub.4)                                                            J = 9.5 Hz)                                           30    R.sup.1 = C.sub.2 H.sub.5                                                                       m/z: 696 (M.sup.+)                                          R.sup.2 = H       NMR: 3.59 (1 H, d,                                          R.sup.3 = CO-(m-Cl--C.sub.6 H.sub.4)                                                            J = 9.5 Hz)                                           31    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (2.2:1)                                                    m/z: 788 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = CO-(p-I--C.sub.6 H.sub.4)                                                             NMR: 3.57 (1 H, d,                                                            J = 9.2 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.59 (1 H, d,                                            J = 9.2 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            32    R.sup.1 = C.sub.2 H.sub.5                                                                       m/z: 676 (M.sup.+)                                          R.sup.2 = H       NMR: 3.58 (1 H, d,                                                            J = 9.5 Hz)                                                 R.sup.3 = CO-(p-CH.sub.3 --C.sub.6 H.sub.4)                             33    R.sup.1  = C.sub.2 H.sub.5 + CH.sub.3 (2.3:1)                                                   m/z: 629 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = CO-(p-OCH.sub.3 --                                                                    NMR: 3.57 (1 H, d,                                          C.sub.6 H.sub.4)  J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.58 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            34    R.sup.1 = C.sub.2 H.sub.5                                                                       m/z: 730 (M.sup.+, assigned to                              R.sup.2 = H       Cl = 35)                                                    R.sup.3 = CO-(2,4-diCl--                                                                        NMR: 3.59 (1 H, d,                                          C.sub.6 H.sub.3)  J = 9.5 Hz)                                           35    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (2.3:1)                                                    m/z: 726 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 =  COCH.sub.2 O-(p-Cl--                                                                 NMR: 3.56 (1 H, d,                                          C.sub.6 H.sub.4)  J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.57 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            36    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (2.3:1)                                                    m/z: 709 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = COCH.sub.2 OCO-                                                                       NMR: 3.55 (1 H, d,                                          (2-pyrrolyl)      J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.56 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            37    R.sup.1 = C.sub.2 H.sub.5                                                                       m/z: 668 (M.sup.+)                                          R.sup.2 = H       NMR: 3.58 (1 H, d,                                          R.sup.3 = 2-thenoyl                                                                             J = 9.5 Hz)                                           38    R.sup. 1 = C.sub.2 H.sub.5                                                                      m/z: 696 (M.sup.+)                                          R.sup.2 = H       NMR: 3.59 (1 H, d,                                          R.sup.3 = CO-(o-Cl--C.sub.6 H.sub.4)                                                            J = 9.5 Hz)                                           39    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (2.5:1)                                                    m/z: 680 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = CO-(p-F--C.sub.6 H.sub.4)                                                             NMR: 3.58 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.59 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            40    R.sup.1 = C.sub.2 H.sub.5                                                                       m/z: 680 (M.sup.+)                                          R.sup.2 = H       NMR: 3.59 (1 H, d,                                          R.sup.3 = CO-(o-F--C.sub.6 H.sub.4)                                                             J = 9.5 Hz)                                           41    R.sup.1 = C.sub.2 H.sub.5                                                                       m/z: 663 (M.sup.+)                                          R.sup.2 = H       NMR: 3.59 (1 H, d,                                          R.sup.3 = isonicotinoyl                                                                         J = 9.2 Hz)                                           42    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (2.2:1)                                                    m/z: 680 (M.sup.+, assigned to                              R.sup.2 = H       R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.3 = CO-(m-F--C.sub.6 H.sub.4)                                                             NMR: 3.58 (1 H, d,                                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.59 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                            43    R.sup.1 = C.sub.2 H.sub.5                                                                       m/z: 707 (M.sup.+)                                          R.sup.2 = H       NMR: 3.60 (1 H, d,                                          R.sup.3 = CO-(p-NO.sub.2 --C.sub.6 H.sub.4)                                                     J = 9.5 Hz)                                           ______________________________________                                    

EXAMPLE 44 8,9-Epoxy-5-O-thiocyanatoacetylmilbemycin A₄₊₃ [R¹ =C₂ H₅+CH₃ (2.6:1), R² =H, R³ =COCH₂ SCN]

A solution of 100 mg of 8,9-epoxy-5-O-bromacetylmilbemycin A₄₊₃(prepared as in Example 13) and 15 mg of potassium rhodanide in 0.5 mlof acetone was mixed with a catalytic amount of sodium iodide andallowed to react at room temperature for 3 hours. The mixture was pouredinto water and extracted with ethyl acetate. The extracts were washedwith water and then with a saturated aqueous solution of sodium chlorideand dried over anhydrous magnesium sulfate. The solvent was then removedby distillation under reduced pressure and the residue was subjected tocolumn chromatography through silica gel, to give 7.21 mg of the titlecompound.

Mass spectrum (m/z): 657 (M⁺, assigned to R¹ =C₂ H₅).

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃), C₉ H, δ ppm:

3.56 (1H, doublet, J=9.5 Hz, assigned to R¹ =CH₃);

3.58 (1H, doublet, J=9.5 Hz, assigned to R¹ =C₂ H₅).

EXAMPLE 45 8,9-Epoxy-5-O-trifluoroacetylmilbemycin A₄ (R¹ =C₂ H₅, R² =H,R³ =COCF₃)

38 μl of trifluoroacetic anhydride were added to a solution of 100 mg of8,9-epoxymilbemycin A₄ and 28.3 mg of pyridine in 20 ml of dry benzene,whilst ice-cooling, and the mixture was allowed to react at roomtemperature for 30 minutes. At the end of this time, the reactionmixture was poured into an aqueous solution of sodium bicarbonate andextracted with ethyl acetate. The extracts were washed with water anddried over anhydrous magnesium sulfate. The solvent was then removed bydistillation under reduced pressure, and the residue was subjected tocolumn chromatography through silica gel, to give 71.0 mg of the titlecompound.

Mass Spectrum (m/z): 654 (M⁺)

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃), C₉ H, δ ppm:

3.58 (1H, doublet, J=9.5 Hz).

EXAMPLE 46 8,9-Epoxy-5-O-(3-carboxypropionyl)milbemycin A₄ (R¹ =C₂ H₅,R² =H, R³ =COCH₂ CH₂ COOH)

100 mg of 8,9-epoxymilbemycin A₄, 54 mg of triethylamine and 27 mg ofsuccinic anhydride were reacted in the same way as described in Example45, to give 110 mg of the title compound.

Mass spectrum (m/z): 558 (M⁺ +1-COCH₂ CH₂ COOH).

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃), δ ppm:

2.6-2.8 (4H, multiplet, COCH₂ CH₂ COOH);

3.56 (1H, doublet, J=9.8 Hz, C₉ H).

EXAMPLE 47 14,15-Epoxy-5-O-propionylmilbemycin A₄₊₃ [R¹ =C₂ H₅ +CH₃(3.3:1), R² =H, R³ =COC₂ H₅ ]

94 mg of m-chloroperbenzoic acid were added to a solution of 240 mg of5-O-propionylmilbemycin A₄₊₃ (3:1) in 10 ml of dry methylene chloride,whilst ice-cooling, and the mixture was allowed to react at roomtemperature for 2 hours. At the end of this time, the reaction mixturewas filtered and the filtrate was washed with an aqueous solution ofsodium bicarbonate. The solvent was then removed by distillation underreduced pressure, and the residue was subjected to column chromatographythrough silica gel, to give 160 mg of the title compound.

Mass spectrum (m/z): 614 (M⁺, assigned to R¹ =C₂ H₅).

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:

2.59 (1H, doublet, J=9.2 Hz, C₁₅ H);

5.75-5.95 (2H, multiplet, C₉ H, C₁₀ H).

Following a procedure similar to that described in Example 47, thecompounds of Examples 48 and 49 were prepared

EXAMPLE 48 14,15-Epoxy-5-O-acetylmilbemycin A₄₊₃ [R¹ =C₂ H₅ +CH₃(2:5:1), R² =H, R³ =COCH₃ ]

Mass spectrum (m/z): 600 (M⁺, assigned to R¹ =C₂ H₅).

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:

2.54 (1H, doublet, J=9.3 Hz, C₁₅ H).

EXAMPLE 49 14,15-Epoxy-5-O-methylcarbamoylimilbemycin A₄ (R¹ =C₂ H₅, R²=H, R³ =CONHCH₃)

Mass spectrum (m/z): 615 (M⁺).

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:

2.61 (1H, doublet, J=9.3 Hz, C₁₅ H).

EXAMPLE 50 8,9:14,15-Diepoxy-5-O-chloromethoxycarbonylmilbemycin A₄ (R¹=C₂ H₅, R² =H, R³ =COOCH₂ Cl)

10 mg of m-chloroperbenzoic acid were added to a solution of 32 mg of8,9-epoxy-5-O-chloromethoxycarbonylmilbemycin A₄ (prepared as in Example18) in 1.1 ml of dry methylene chloride, whilst ice-cooling, and themixture was allowed to react at room temperature for 5 hours. At the endof this time, the reaction mixture was filtered and the filtrate waswashed with an aqueous solution of sodium bicarbonate. The solvent wasthen removed by distillation under reduced pressure and the residue wassubjected to column chromatography through silica gel, to give 13 mg ofthe title compound.

Mass spectrum (m/z): 666 (M⁺, assigned to Cl=35).

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl₃) δ ppm:

2.66 (1H, doublet, J=9.9 Hz, C₁₅ H):

3.53 (1H, doublet, J=9.5 Hz, C₉ H).

Following a procedure similar to that described in Example 50, thefollowing compounds of formula (Ib): ##STR7## in which R¹, R² and R³ areas defined in the following Table, were prepared. The nuclear magneticresonance spectrum are reported only for the hydrogen atoms at C₉ andC₁₅.

    ______________________________________                                              R.sup.1                                                                 Exam- R.sup.2           m/z                                                   ples  R.sup.3           NMR (C.sub.9 H and C.sub.15 H)                        ______________________________________                                        51    R.sup.1 = C.sub.2 H.sub.5                                                                       m/z: 650 (M.sup.+, assigned                                 R.sup.2 = H       to Cl = 35)                                                 R.sup.3 = COCH.sub.2 Cl                                                                         C.sub.9 H: 3.42 (1 H, d,                                                      J = 9.35 Hz),                                                                 C.sub.15 H: 2.55 (1 H, d,                                                     J = 9.5 Hz)                                           52    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (4:1)                                                      m/z: 664 (M.sup.+, assigned to                                                R.sup.1 = C.sub.2 H.sub.5 & Cl = 35)                        R.sup.2 = H       C.sub.9 H: 3.53 (1 H, d,                                                      J = 9.5 Hz)                                                 R.sup.3 = COCHClCH.sub.3                                                                        C.sub.15 H: 2.66 (1 H, d,                                                     J = 9.2 Hz)                                           53    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (1.7:1)                                                    m/z: 556 (M .sup. +  + 1 -                                  R.sup.2 = H       COC.sub.6 H.sub.5 --H.sub.2 O, assigned                                       to R.sup.1 = C.sub.2 H.sub.5)                               R.sup.3 = COC.sub.6 H.sub.5                                                                     C.sub.9 H: 3.54 (1 H, d,                                                      J = 9.5 Hz, assigned to                                                       R.sup.1 = CH.sub.3), 3.56 (1 H, d,                                            J = 9.5 Hz, assigned to                                                       R.sup.1 = C.sub.2 H.sub.5)                                                    C.sub.15 H: 2.66 (1 H, d,                                                     J = 9 Hz)                                             54    R.sup.1 = C.sub.2 H.sub.5 + CH.sub.3 (2.6:1)                                                    m/z: 616 (M.sup.+, assigned to                                                R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.2 = H       C.sub.9 H: 3.54 (1 H, d,                                                      J = 9 Hz)                                                   R.sup.3 = COCH.sub.3                                                                            C.sub.15 H: 2.63 (1 H, d,                                                     J = 9.5 Hz)                                           55    C.sub.2 H.sub.5  + CH.sub.3 (2.6:1)                                                             m/z: 630 (M.sup.+, assigned to                                                R.sup.1 = C.sub.2 H.sub.5)                                  R.sup.2 = H       C.sub.9 H: 3.52 (1 H, d,                                                      J = 9.5 Hz)                                                 R.sup.3 = COC.sub.2 H.sub.5                                                                     C.sub.15 H: 2.66 (1 H, d,                                                     J = 9.9 Hz)                                           ______________________________________                                    

EXAMPLE 56 Acaricidal activity against Tetranychus urticae

The primary leaves of cowpea plants of the species Vigna sinensis Saviwere infected with organic phosphate-sensitive mites (Tetranychusurticae). One day after infection, the infested plants were sprayed,using a Mizuho rotary sprayer, with 7 ml of a test solution containingthe compound under test at a concentration of 3 ppm, at a rate of 3.5 mgof the test solution per 1 cm² of leaf. The plants were assessed after 3days by examining adult mites, under a binocular microscope, todetermine living and dead individuals. Two plants were used for eachconcentration and each test compound. The plants were kept during thetest in greenhouse compartments at 25° C. The results are reported inthe following Table.

    ______________________________________                                        Compound of Example No.                                                                           Lethal (%)                                                ______________________________________                                         1                  98                                                         2                  100                                                       12                  56                                                        15                  100                                                       17                  94                                                        18                  97                                                        21                  94                                                        22                  60                                                        24                  69                                                        32                  73                                                        35                  86                                                        37                  77                                                        45                  100                                                       48                  67                                                        52                  71                                                        54                  71                                                        55                  99                                                        Control Compound 1  40                                                        Control Compound 2  45                                                        Control Compound 3  33                                                        Control Compound 4  31                                                        Control Compound 5  17                                                        Control Compound 6  63                                                        Control Compound 7  21                                                        ______________________________________                                    

The Control compounds were as follows:

1. Milbemycin A₄

2. 8,9-Epoxymilbemycin A₄

3. 14,15-Epoxymilbemycin A₄

4. 8,9:14,15-Diepoxymilbemycin A₄

5. 5-O-acetylmilbemycin A₄

6. 5-O-propionylmilbemycin A₄₊₃ (3:1)

7. 5-O-chloroacetylmilbemycin A₄₊₃ (3:1)

As can be seen clearly from the above results, the compounds of thepresent invention have a far stronger acaricidal activity than that ofnatural milbemycin A₄ as well as stronger activities than thecorresponding unesterified epoxymilbemycins or unepoxidizedacylmilbemycins.

In more detail, the acaricidal effect of Control Compound 2 (in whichmilbemycin A₄, Control Compound 1, was epoxidized at the 8,9 position)was intensified slightly from 40% for Control Compound 1 to 45% forControl Compound 2, whilst the acaricidal effect of Control Compound 5(the acetylated derivative of Control Compound 1) was actually reducedfrom the value of 40% achieved for Control Compound 1 to 17% for ControlCompound 5. On the contrary, the acaricidal effect of the compound ofExample 1 of the present invention was remarkably improved from the 40%of Control Compound 1 to 98%.

EXAMPLE 57 Nematocidal Activity Against Nippostrongylus Brasiliensis

0.1 ml of an aqueous solution containing the compound under test at avariety of concentration was added to 0.4 ml of a suspension oftrichogenous nematodes (Nippostrongylus brasiliensis) which areparasitic on wild rats and had been previously cultured and hatched. 24hours after this addition, the motility of the nematodes was checked bymicroscopic examination and the minimum inhibitory concentrations (MIC)of each of the test compounds was calculated. The MIC values for thecompounds of Examples 1 and 15 were both 1.25 μg/ml, whilst those of thecompounds of Examples 2, 45 and 47 were all 0.63 μg/ml.

We claim:
 1. A compound of formula (I): ##STR8## in which: the brokenline represents a single or double carbon-carbon bond between the carbonatoms at the 22 and 23 positions:R¹ represents an isopropyl group or asec-butyl group; R² represents a 4'-(α-L-oleandrosyl)-α-L-oleandrosyloxygroup; A represents an oxygen atom; B represents a double bond betweenthe two carbon atoms to which it is shown as attached; and R³ representsa group of formula:

    --CO--(O).sub.n --R.sup.4

in which: n represents the cypher 0 or the integer 1; and R⁴ representsa C₁ -C₁₈ alkyl group, a C₃ -C₈ cycloalkyl group, a C₇ -C₉ aralkylgroup, a C₂ -C₁₇ alkenyl group, a C₂ -C₆ alkynyl group, a C₆ -C₁₀ arylgroup of a heterocyclic group having from 5 to 10 ring atoms of which atleast one is a hetero-atom selected from the group consisting ofnitrogen, oxygen and sulfur atoms, said alkyl, alkenyl and alkynylgroups being unsubstituted or having at least one substituent selectedfrom the group consisting of substituents (a):substituents (a): alkoxygroups, halogen atoms, alkoxycarbonyl groups, carboxylic acyloxy groups,hydroxy groups, carboxy groups, amino groups, alkylamino groups,dialkylamino groups, trialkylamino groups, carboxylic acylamino groups,cyano groups, carbamoyl groups, alkylcarbamoyl groups, dialkylcarbamoylgroups, mercapto groups, alkylthio groups, alkylsulfinyl groups,alkylsulfonyl groups, nitro groups, phenoxy groups, halophenoxy groups,alkylsulfonyloxy groups, arylsulfonyloxy groups, thiocyanato groups andheterocyclic groups having 5 or 6 ring atoms of which at least one is ahetero-atom selected from the group consisting of nitrogen, oxygen andsulfur atoms; and said cycloalkyl, aralkyl and aryl groups beingunsubstituted or having at least one substituent selected from the groupconsisting of substituents (a) and substituents (b):substituents (b):alkyl groups, alkoxyalkyl groups and haloalkyl groups; and saidheterocyclic groups being unsubstituted or having at least onesubstituent selected from the group consisting of substituents (a),substituents (b) and oxygen atoms; where groups in said substituents (a)and substituents (b) contain carbon atoms, the maximum number of carbonatoms in each such group is 9 and said groups defined in substituents(a) and substituents (b) being unsubstituted or having at least onefurther substituent selected from the group consisting of substituents(a) and substituents (b) provided said further substituent is not itselffurther substituted; or R³ represents a group of formula:

    --CO--NR.sup.5 R.sup.6

in which R⁵ and R⁶ are independently selected from the group consistingof hydrogen atoms, C₁ -C₆ alkyl groups, C₂ -C₆ alkenyl groups, C₇ -C₉aralkyl groups and C₆ -C₁₀ aryl groups, said groups being unsubstitutedor having at least one substituent selected, in the case of said alkyland alkenyl groups, from the group consisting of substituents (a) and,in the case of said aralkyl and aryl groups, from the group consistingof substituents (a) and substituents (b):substituents (a): alkoxygroups, halogen atoms, alkoxycarbonyl groups, carboxylic acyloxy groups,hydroxy groups, carboxy groups, amino groups, alkylamino groups,dialkylamino groups, trialkylamino groups, carboxylic acylamino groups,cyano groups, carbamoyl groups, alkylcarbamoyl groups, dialkylcarbamoylgroups, mercapto groups, alkylthio groups, alkylsulfinyl groups,alkylsulfonyl groups, nitro groups, phenoxy groups, halophenoxy groups,alkylsulfonyloxy groups, arylsulfonyloxy groups, thiocyanato groups andheterocyclic groups having 5 or 6 ring atoms of which at least one is ahetero-atom selected from the group consisting of nitrogen, oxygen andsulfur atoms; substituents (b): alkyl groups, alkoxyalkyl groups andhaloalkyl groups; where groups in said substituents (a) and substituents(b) contain carbon atoms, the maximum number of carbon atoms in eachsuch group is 9 and said groups defined in substituents (a) andsubstituents (b) being unsubstituted or having at least one furthersubstituent selected from the group consisting of substituents (a) andsubstituents (b) provided said further substituent is not itself furthersubstituted; or R³ represents a group of formula:

    --SO.sub.2 R.sup.7

in which R⁷ represents a C₁ -C₆ alkyl group or a C₆ -C₁₀ aryl group,said groups being unsubstituted or having at least one substituentselected, in the case of said alkyl group, from the group consisting ofsubstituents (a) and, in the case of said aryl group, from the groupconsisting of substituents (b):substituents (a): alkoxy groups, halogenatoms, alkoxycarbonyl groups, carboxylic acyloxy groups, hydroxy groups,carboxy groups, amino groups, alkylamino groups, dialkylamino groups,trialkylamino groups, carboxylic acylamino groups, cyano groups,carbamoyl groups, alkylcarbamoyl groups, dialkylcarbamoyl groups,mercapto groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonylgroups, nitro groups, phenoxy groups, halophenoxy groups,alkylsulfonyloxy groups, arylsulfonyloxy groups, thiocyanato groups andheterocyclic groups having 5 or 6 ring atoms of which at least one is ahetero-atom selected from the group consisting of nitrogen, oxygen andsulfur atoms; substituents (b): alkyl groups, alkoxyalkyl groups andhaloalkyl groups; where groups in said substituents (a) and substituents(b) contain carbon atoms, the maximum number of carbon atoms in eachsuch group is 9 and said group defined in substituents (a) andsubstituents (b) being unsubstituted or having at least one furthersubstituent selected from the group consisting of substituents (a) andsubstituents (b) provided said further substituent is not itself furthersubstituted; or R³ represents a group of formula:

    --(Y.sup.1 ═)P(--Y.sup.2 --R.sup.8)--Y.sup.3 --R.sup.9

in which: Y¹, Y² and Y³ are independently selected from the groupconsisting of oxygen atoms and sulfur atoms; and R⁸ and R⁹ areindependently selected from the group consisting of C₁ -C₆ alkyl groupsand C₁ -C₆ alkyl groups having at least one substituent selected fromthe group consisting of substituents (a):substituents (a): alkoxygroups, halogen atoms, alkoxycarbonyl groups, carboxylic acyloxy groups,hydroxy groups, carboxy groups, amino groups, alkylamino groups,dialkylamino groups, trialkylamino groups, carboxylic acylamino groups,cyano groups, carbamoyl groups, alkylcarbamoyl groups, dialkylcarbamoylgroups, mercapto groups, alkylthio groups, alkylsulfinyl groups,alkylsulfonyl groups, nitro groups, phenoxy groups, halophenoxy groups,alkylsulfonyloxy groups, arylsulfonyloxy groups, thiocyanato groups andheterocyclic groups having 5 or 6 ring atoms of which at least one is ahetero-atom selected from the group consisting of nitrogen, oxygen andsulfur atoms; where groups in said substituents (a) contain carbonatoms, the maximum number of carbon atoms in each such group is 9 andsaid groups defined in substituents (a) being unsubstituted or having atleast one further substituent selected from the group consisting ofsubstituents (a) and substituents (b) provided said further substituentis not itself further substituted;substituents (b): alkyl groups,alkoxyalkyl groups and haloalkyl groups; or R³ is selected from thegroup consisting of acetyl, propionyl, chloroacetyl, trichloroacetyl,trifluoroacetyl, acetoxyacetyl, chloropropionyl, chlorobenzoyl,ethoxycarbonyl, methoxycarbonyl, chloromethoxycarbonyl,dichloromethoxycarbonyl,(3,4-dihydro-2H-pyran-2-carbonyloxy)methoxycarbonyl,(3,4,5,6-diisopropylidene-D-galactouronyloxy)methoxycarbonyl,(2,2-dimethyl-1,3-dioxolanylmethoxy)methoxycarbonyl,hydroxybutyryloxymethoxycarbonyl, carboxypropionyl,(1H-1,2,4-triazol-1-yl)acetyl, diethylaminoacetyl,(iodomethyldiethylammonio)acetyl, methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl, methanesulfonyl, p-toluenesulfonyl,benzenesulfonyl, diethylthiophosphoryl, dimethylphosphoryl,diethylphosphoryl, fluorobenzoyl, butyryl, valeryl, hexanoyl, octanoyl,hexadecanoyl, isobutyryl, isovaleryl, pivaloyl, acryloyl, benzoyl,bromoacetyl, allyloxycarbonyl, iodoacetyl, propionyloxyacetyl,hydroxyacetoxyacetyl, (benzamidoacetoxy)acetyl, cinnamoyl,(trifluoromethyl)benzoyl, iodobenzoyl, toluoyl, methoxybenzoyl,dichlorobenzoyl, (chlorobenzyloxy)acetyl, (pyrrolylcarbonyloxy)acetyl,fluorobenzoyl, nicotinoyl, isonicotinoyl, picolinoyl, nitrobenzoyl andthiocyanatoacetyl groups.
 2. A compound of formula (I): ##STR9## inwhich: the broken line represents a single or double carbon-carbon bondbetween the carbon atoms at the 22 and 23 positions;R¹ represents amethyl group, an ethyl group, an isopropyl group or a sec-butyl group;R² represents a hydrogen atom or a4'-(α-L-oleandrosyl)-α-L-oleandrosyloxy group; A represents an oxygenatom; B represents a double bond between the two carbon atoms to whichit is shown as attached; and R³ represents a group of formula:

    --CO--NR.sup.5 R.sup.6

in which R⁵ and R⁶ are independently selected from the group consistingof hydrogen atoms, C₁ -C₆ alkyl groups, C₂ -C₆ alkenyl groups, C₇ -C₉aralkyl groups and C₆ -C₁₀ aryl groups, said groups being unsubstitutedor having at least one substituent selected, in the case of said alkyland alkenyl groups, from the group consisting of substituents (a) and,in the case of said aralkyl and aryl groups, from the group consistingof substituents (a) and substituents (b):substituents (a): alkoxygroups, halogen atoms, alkoxycarbonyl groups, carboxylic acyloxy groups,hydroxy groups, carboxy groups, amino groups, alkylamino groups,dialkylamino groups, trialkylamino groups, carboxylic acylamino groups,cyano groups, carbamoyl groups, alkylcarbamoyl groups, dialkylcarbamoylgroups, mercapto groups, alkylthio groups, alkylsulfinyl groups,alkylsulfonyl groups, nitro groups, phenoxy groups, halophenoxy groups,alkylsulfonyloxy groups, arylsulfonyloxy groups, thiocyanato groups andheterocyclic groups having 5 or 6 ring atoms of which at least one is ahetero-atom selected from the group consisting of nitrogen, oxygen andsulfur atoms; substituents (b): alkyl groups, alkoxyalkyl groups andhaloalkyl groups; where groups in said substituents (a) and substituents(b) contain carbon atoms, the maximum number of carbon atoms in eachsuch group is 9 and said groups defined in substituents (a) andsubstituents (b) being unsubstituted or having at least one furthersubstituent selected from the group consisting of substituents (a) andsubstituents (b) provided said further substituent is not itself furthersubstituted.
 3. A compound of formula (I): ##STR10## in which: thebroken line represents a single or double carbon-carbon bond between thecarbon atoms at the 22 and 23 positions;R¹ represents a methyl group, anethyl group, an isopropyl group or a sec-butyl group; R² represents ahydrogen atom or a 4'-(α-L-oleandrosyl)-α-L-oleandrosyloxy group; Arepresents an oxygen atom; B represents double bond between the twocarbon atoms to which it is shown as attached; and R³ represents a groupof formula:

    --SO.sub.2 R.sup.7

in which R⁷ represents a C₁ -C₆ alkyl group or a C₆ -C₁₀ aryl group,said groups being unsubstituted or having at least one substituentselected, in the case of said alkyl group, from the group consisting ofsubstituents (a) and, in the case of said aryl group, from the groupconsisting of substituents (b):substituents (a): alkoxy groups, halogenatoms, alkoxycarbonyl groups, carboxylic acyloxy groups, hydroxy groups,carboxy groups, amino groups, alkylamino groups, dialkylamino groups,trialkylamino groups, carboxylic acylamino groups, cyano groups,carbamoyl groups, alkylcarbamoyl groups, dialkylcarbamoyl groups,mercapto groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonylgroups, nitro groups, phenoxy groups, halophenoxy groups,alkylsulfonyloxy groups, arylsulfonyloxy groups, thiocyanato groups andheterocyclic groups having 5 or 6 ring atoms of which at least one is ahetero-atom selected from the group consisting of nitrogen, oxygen andsulfur atoms; substituents (b): alkyl groups, alkoxyalkyl groups andhaloalkyl groups; where groups in said substituents (a) and substituents(b) contain carbon atoms, the maximum number of carbon atoms in eachsuch group is 9 and said groups defined in substituents (a) andsubstituents (b) being unsubstituted or having at least one furthersubstituent selected from the group consisting of substituents (a) andsubstituents (b) provided said further substituent is not itself furthersubstituted.
 4. A compound of formula (I): ##STR11## in which: thebroken line represents a single or double carbon-carbon bond between thecarbon atoms at the 22 and 23 positions;R¹ represents a methyl group, anethyl group, an isopropyl group of a sec-butyl group; R² represents ahydrogen atom or a 4'-(α-L-oleandrosyl)-α-L-oleandrosyloxy group; Arepresents an oxygen atom; B represents a double bond between the twocarbon atoms to which it is shown as attached; and R³ represents a groupof formula:

    --(Y.sup.1 ═)P(--Y.sup.2 --R.sup.8)--Y.sup.3 --R.sup.9

in which: Y¹, Y² and Y³ are independently selected from the groupconsisting of oxygen atoms and sulfur atoms; and R⁸ and R⁹ areindependently selected from the group consisting of C₁ -C₆ alkyl groupsand C₁ -C₆ alkyl groups having at least one substituent selected fromthe group consisting of substituents (a):substituents (a): alkoxygroups, halogen atoms, alkoxycarbonyl groups, carboxylic acyloxy groups,hydroxy groups, carboxy groups, amino groups, alkylamino groups,dialkylamino groups, trialkylamino groups, carboxylic acylamino groups,cyano groups, carbamoyl groups, alkylcarbamoyl groups, dialkylcarbamoylgroups, mercapto groups, alkylthio groups, alkylsulfinyl groups,alkylsulfonyl groups, nitro groups, phenoxy groups, halophenoxy groups,alkylsulfonyloxy groups, arylsulfonyloxy groups, thiocyanato groups andheterocyclic groups having 5 or 6 ring atoms of which at least one is ahetero-atom selected from the group consisting of nitrogen, oxygen andsulfur atoms; where groups in said substituents (a) contain carbonatoms, the maximum number of carbon atoms in each such group is 9 andsaid groups defined in substituents (a) being unsubstituted or having atleast one further substituent selected from the group consisting ofsubstituents (a) and substituents (b) provided said further substituentis not itself further substituted;substituents (b): alkyl groups,alkoxyalkyl groups and haloalkyl groups.
 5. A compound as claimed inclaim 1, wherein the broken line between the 22 and 23 positionsrepresents a single bond, R¹ represents an isopropyl group or asec-butyl group and R² represents a4'-(α-L-oleandrosyl)-α-L-oleandrosyloxy group.
 6. A compound as claimedin claim 1, wherein the broken line between the 22 and 23 positionsrepresents a double bond, R¹ represents an isopropyl group or asec-butyl group and R² represents a4'-(α-L-oleandrosyl)-α-L-oleandrosyloxy group.
 7. A compound as claimedin claim 1, wherein R³ represents a group of formula:

    --(Y.sup.1 ═)P(--Y.sup.2 --R.sup.8)--Y.sup.3 --R.sup.9

in which: Y¹, Y² and Y³ are independently selected from the groupconsisting of oxygen atoms and sulfur atoms; and R⁸ and R⁹ areindependently selected from the group consisting of C₁ -C₆ alkyl groupsand C₁ -C₆ alkyl groups having at least one substituent selected fromthe group consisting of substituents (a):substituents (a): alkoxygroups, halogen atoms, alkoxycarbonyl groups, carboxylic acyloxy groups,hydroxy groups, carboxy groups, amino groups, alkylamino groups,dialkylamino groups, trialkylamino groups, carboxylic acylamino groups,cyano groups, carbamoyl groups, alkylcarbamoyl groups, dialkylcarbamoylgroups, mercapto groups, alkylthio groups, alkylsulfinyl groups,alkylsulfonyl groups, nitro groups, phenoxy groups, halophenoxy groups,alkylsulfonyloxy groups, arylsulfonyloxy groups, thiocyanato groups andheterocyclic groups having 5 or 6 ring atoms of which at least one is ahetero-atom selected from the group consisting of nitrogen, oxygen andsulfur atoms; where groups in said substituents (a) contain carbonatoms, the maximum number of carbon atoms in each such group is 9 andsaid groups defined in substituents (a) being unsubstituted or having atleast one further substituent selected from the group consisting ofsubstituents (a) and substituents (b) provided said further substituentis not itself further substituted;substituents (b): alkyl groups,alkoxyalkyl groups and haloalkyl groups.
 8. A compound designated8,9-epoxy-5-O-propionylmilbemycin A₄₊₃.
 9. A compound designated8,9-epoxy-5-O-α-chloropropionylmilbemycin A₄₊₃.
 10. A compounddesignated 8,9-epoxy-5-O-trifluoroacetylmilbemycin A₄.
 11. Ananti-parasitic composition comprising an anti-parasitic effective amountof the compound of claim 2 in an acceptable carrier.
 12. Ananti-parasitic composition comprising an anti-parasitic effective amountof the compound of claim 3 in an acceptable carrier.
 13. Ananti-parasitic composition comprising an anti-parasitic effective amountof the compound of claim 4 in an acceptable carrier.
 14. A method oftreating a plant against damage by parasites selected from the groupconsisting of acarids, helminths and insects which comprise applying aneffective amount of the compound of claim 2 to said plant or the seedsof said plant.
 15. A method of treating a plant against damage byparasites selected from the group consisting of acarids, helminths andinsects which comprise applying an effective amount of the compound ofclaim 3 to said plant or the seeds of said plant.
 16. A method oftreating a plant against damage by parasites selected from the groupconsisting of acarids, helminths and insects which comprise applying aneffective amount of the compound of claim 4 to said plant or the seedsof said plant.
 17. A method of treating an animal against damage byparasites selected from the group consisting of acarids, helminths andinsects which comprise applying an effective amount of the compound ofclaim 2 to said animal.
 18. A method of treating an animal againstdamage by parasites selected from the group consisting of acarids,helminths and insects which comprise applying an effective amount of thecompound of claim 3 to said animal.
 19. A method of treating an animalagainst damage by parasites selected from the group consisting ofacarids, helminths and insects which comprise applying an effectiveamount of the compound of claim 4 to said animal.